Gonadotropin-releasing hormone (GnRH) neurons are required for the establishment and maintenance of fertility in all vertebrates. Previous studies have shown that there is little or no age-dependent decline in the number of GnRH neurons in normal rodents. However, we have shown that mice with the targeted disruption of fibroblast growth factor receptor (FGFR) function in GnRH neurons (termed 'dnFGFR'animals) suffer a significant age-dependent loss of GnRH neurons. Because 10-20% of hypogonadotropic hypogonadal human patients harbor mutations leading to FGF signaling deficiency, we are interested in using this rodent model to investigate if the postnatal loss of GnRH neurons can be restored by environmental stimulation. Excitingly, our preliminary data suggest that pairing of aged male dnFGFR mice with females could significantly rescue the failing GnRH system in males, possibly by reactivating these neurons. In the proposed study, we will test the central hypothesis that sexual stimuli (i.e. opposite-sex housing) can restore the GnRH system in a mouse model suffering from an age-dependent postnatal loss of the GnRH system. The specific aims are to: 1) determine the time course of GnRH system rescue in males and females housed with opposite sexes in dnFGFR mice;2) elucidate which environmental stimuli are involved in the rescue of the GnRH system;and 3) determine the mechanism(s) involved in the rescue of the GnRH system. If our central hypothesis is supported, our data would provide compelling evidence, for the first time, that the maintenance of a postnatal neuroendocrine brain is a highly plastic event that responds robustly to environmental stimuli. Further, results from these studies suggest that lifestyle changes may be sufficient for the restoration of failing reproductive function in aging individuals, and may shed light on how environmental factors could rescue neuronal functions in other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Human infertility is on the rise in the US, likely due to the fact that many couples are choosing to reproduce later in life. This infertility is, in part, due to brain hormone (neuroendocrine) deficiencies, which can accelerate reproductive aging, such as hypogonadotropic hypogonadism (HH, decreased hormone signaling and reduced gonad size, absent puberty and/or infertility, due to neuroendocrine deficiencies). HH occurrence in humans is due to genetic and environmental factors, including fibroblast growth factor (FGF)-signaling deficiencies. Further, because HH exhibits a wide variety of phenotypes, it is probable that there is an even larger population of individuals that unknowingly harbor FGF mutations with milder reproductive phenotypes. In these individuals, reproductive dysfunction may increase as the individual ages, and certain stressors may exacerbate this reproductive dysfunction. Lastly, a common paradigm in brain aging research is that the reactivation of neurons prevents or reverses neurodegenerative diseases. Our studies suggest a surprisingly simple and novel solution for reactivating the aging neuroendocrine system and maintaining fertility in older individuals: cohabitation (and/or sexual interaction) with the opposite sex. Thus, our studies are not only relevant for HH and infertility in humans, but may shed light on the role of environmental factors on the reactivation of neurons in other neurodegenerative diseases.